Medicinal composition

ABSTRACT

The present invention relates to an ameliorant for improving the movement of the digestive tract comprising, as an active ingredient, 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pirrolidinyl]benzamide or an acid addition salt thereof which is a metabolite of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof, having high biding affinity for a serotonin receptor 4 (5HT 4 ) and causing no arteritis and thrombus formation; a medicinal composition for improving the movement of the digestive tract comprising the said ameliorant and a pharmaceutically acceptable carrier; and a treating method for promoting the movement of the digestive tract, which comprises using the said medicinal composition for improving the movement of the digestive tract.

TECHNICAL FIELD

The present invention relates to an ameliorant for improving themovement of the digestive tract of a human and an animal containing asan active ingredient a compound which is suitable for activating themovement of the digestive tract, inter alia, stomach to rapidlyeliminate abnormal retention of an ingested food in the organ, has aperipheral acting site, and has no side effect such as arteritis, thatis,4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, a medicinal composition comprising theactive ingredient and a pharmaceutically acceptable carrier, a methodfor improving disorder of the movement dysfunction of the digestivetract comprising administering a composition containing an effectiveamount of the active compound to a patient, and use of the compound forpreparing the composition.

BACKGROUND TECHNIQUE

A compound having a generic name of metoclopramide is widely known as acompound having nature of promoting the movement of stomach, but inducesextrapyramidal disorder and other undesirable disorders due to action oncentral nervous system. In addition, a compound having a generic name ofcisapride has been put into practice as a digestive tract movementactivator, but use thereof has been stopped due to inducement ofventricular arrhythmia.

4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide(also referred to as TKS159 in some cases) or an acid addition saltthereof which is said to have no or extremely weak action on centralnervous system is known as a compound having action of promoting themovement of the digestive tract, inter alia, stomach (JP-A-17434/1993).However, the present applicant progressed development of TKS159 which isa representative compound of the invention of the above patent and, whenTKS159 was orally administered repeatedly in a safety test using anexperimental animal, inter alia, a beagle dog, findings of disorderssuch as thrombus formation, arteritis, encephalomalacia and the likewere observed. After all, occurrence of such disorders truly shows thatTKS159 is not suitable for use as a medicine. The present inventorsthought that various disorders which had not appeared in a mouse or arat are findings of disorders caused by4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof found to be a metabolite of thecompound specifically produced in a beagle dog and they have repeatedlyadministered 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition saltthereof to a beagle dog. Unexpectedly, it was found out that findings ofvarious disorders seen upon administration of TKS159 were not observed.Moreover, it was found out that4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof is a compound having the ability ofimproving the movement of the digestive tract equivalent to or superiorover that of TKS159 or an acid addition salt thereof. That is, it wasfound out that4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof which can avoid occurrence of disorderssuch as thrombus formation, arteritis, encephalomalacia and the like canbe effectively used as an ameliorant for improving the movement of thedigestive tract containing this compound as an active ingredient.Needless to say, it is natural that desired attribute of a drug used intreatment is sufficient possession of required action, and it is widelysought to provide a drug from which occurrence of not preferable actionwhich is reportedly impossible to avoid due to inevitable attendance tothe drug, has been removed. In diseases other than diseases directlyinfluencing on a life, such the tendency is further intense. It iswidely known that there are many cases where although a drug hassufficient required action, since occurrence of a few unavoidable notpreferable actions can not be avoided, it could not actually play a roleas a therapeutic drug. In addition, although the aforementioned patentdescribes4-amino-5-chloro-2-methoxy-N-(5-hydroxymethylpyrrolidin-3-yl)benzamide,but4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideis a novel compound as stereo isomer or optical isomer.

DISCLOSURE OF THE INVENTION

The present invention has been made based on the aforementionedfindings, and relates to an ameliorant for improving the movement of thedigestive tract, which avoids side effect such as arteritis, containing4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition saltthereof as an active ingredient. Further, the present invention relatesto a novel medicinal composition for administering to a human or amammal (e.g. dog, cat, cow, horse, sheep etc.), comprising the4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, and a pharmaceutically acceptablecarrier.

The ameliorant for improving the movement of the digestive tract of thepresent invention and a novel medicinal composition containing the samerelate to a novel medicinal composition comprising a compound which canavoid side effect concomitantly caused in4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof such as thrombus formation, arteritisand the like, that is,4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide(referred to as TM161 in some cases) or an acid addition salt thereof,and a pharmaceutically acceptable carrier.

The compound TM161 or an acid addition salt thereof was found out as ametabolite of a4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamidecompound or an acid addition salt thereof when administered to a livingbody, inter alia, a beagle dog and, surprisingly it was made clear instudy of the present inventors that the compound or the salt hascharacteristic capable of avoiding occurrence of side effect such asthrombus formation, arteritis and the like which were concomitantlycaused inevitably in administration of

4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide.In addition, it was also made clear that the compound or the salt issuperior over TKS159 or an acid addition salt thereof in the ability toimprove the movement of the digestive tract. Further, it was also madeclear that4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof acts as an agonist such that bindingwith a serotonin 4 (5HT₄) receptor is preferential to binding to otherreceptor, for example, a dopamine D₂ receptor.

Thereby, it has also been elucidated that the compound is a compoundwhich can reduce side effect such as sedative action, extrapyramidaldisorder, exacerbation of prolactin secretion and the like which is saidto be caused by binding with dopamine D₂.

The present invention has been made based on such the various newfindings and, according to the present invention, there are provided anameliorant for improving the movement of the digestive tract containingas an active ingredient4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, which has high binding affinity for aserotonin receptor 4 (5HT₄), and can avoid occurrence of side effectsuch as thrombus formation, arteritis and the like inevitably causedconcomitantly in administration of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, and a medicinal composition containingthe same as an active ingredient, and a pharmaceutically acceptablecarrier. Since it is an indispensable attribute for a medicinalcomposition that side effect is avoided as much as possible, the presentinvention is meaningful.

A true medical invention is first constituted after not only usefulpharmacological activity but also no serious side effect is confirmed.That is, the present invention relates to an ameliorant for improvingthe movement of the digestive tract which has been confirmed to beaneffective and safe medicine not accompanied with occurrence of sideeffect.

The present invention relates to:

(1) an ameliorant for improving the movement of the digestive tractcomprising as an active ingredient4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, which has high binding affinity for aserotonin receptor 4(5HT₄), and does not cause arteritis and thrombusformation,

(2) a medicinal composition for improving the movement of the digestivetract, comprising as an active ingredient4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, which has high binding affinity for aserotonin receptor 4 (5HT₄), and does not cause arteritis and thrombusformation, and a pharmaceutically acceptable carrier,

(3) a treating method for promoting the movement of the digestive tract,which comprises using an ameliorant for improving the movement of thedigestive tract comprising as an active ingredient4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition saltthereof, which is has high binding affinity for a serotonin receptor 4(5HT₄), and does not cause arteritis and thrombus formation, or using amedicinal composition for improving the movement of the digestive tractcomprising the ameliorant and a pharmaceutically acceptable carrier,

(4) a method for improving the movement of the digestive tract of ahuman or an animal, while avoiding occurrence of arteritis, thrombusformation or encephalomalacia, which comprises administering4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition saltthereof, or a medicinal composition comprising the ameliorant and apharmaceutically acceptable carrier to a human or a mammal,

(5)4-amino-5-chloro-2-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidynyl]benzamideor an acid addition salt thereof,

(6)4-amino-5-chloro-2-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamidein which an amino group at position 4 or/and an amino group of thepyrrolidinyl group may be protected, or an acid addition salt thereof,

(7) a process for preparing4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, which comprises reacting4-amino-5-chloro-2-methoxybenzoic acid having an optionally protectedamino group or a reactive derivative thereof with (2S,4S)-4-amino-N-acyl-2-hydroxymethylpyrrolidine to obtain4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-acyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, and eliminating a protecting group andthe acyl group, when a protecting group is used in the acyl group,

(8) (2S,4S)-4-amino-N-acyl-2-hydroxymethylpyrrolidine having anoptionally protected amino group,

(9) the compound according to the above (8), wherein a protecting groupfor an amino group is an acyl group, and the acyl group and an acylgroup of N-acyl are selected from formyl, acetyl, propionyl and benzoyl,and

(10) the compound according to the above (8), wherein the acyl group isacetyl.

The present invention will be explained in more detail below bydescribing embodiments, but they should not be construed as limiting thescope of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a change in binding affinity for a serotonin receptor 4, ofa specimen drug. An abscissa axis indicates a concentration (molarconcentration; logarithmic expression) of a specimen drug, and anordinate axis indicates a ratio of binding of a serotonin receptor 4 and[³H] GR113808. ◯ - - - ◯ indicates a specimen compound obtained inExample 9, and ● - - - ● indicates TKS159 hydrochloride. As aconcentration of a specimen drug grows higher, an amount of [³H]GR113808bound to a serotonin receptor 4 is reduced. That is, it is indicatedthat a specimen drug binds to a serotonin receptor 4, antagonizing[³H]GR113808 binding to the serotonin receptor 4. It is seen thataffinity of a specimen drug obtained in Example 9 for a serotoninreceptor 4 is stronger as compared with affinity of TKS159hydrochloride.

FIG. 2 indicates a change in binding affinity for a dopamine D₂receptor, of a specimen drug. An abscissa axis indicates a concentration(molar concentration; logarithmic expression) of a specimen drug, and anordinate axis indicates a ratio of binding of a dopamine D₂ receptor and[³H]-spiperone. ◯ - - - ◯ indicates a specimen compound obtained inExample 9, and ● - - - ● indicates TKS159 hydrochloride. As aconcentration of a specimen drug grows higher, an amount of[³H]-spiperone bound to a dopamine D₂ receptor is reduced. That is, itis indicated that a specimen drug binds to a dopamine D₂ receptor byantagonizing [³H]-spiperone binding thereto. It is seen that affinity ofa specimen drug obtained in Example 9 for a dopamine D₂ receptor isweaker as compared with affinity of TKS159 hydrochloride.

FIG. 3 indicates a degree of a relaxing reaction of a specimen drug in arat-extracted specimen. An abscissa axis indicates a concentration(molar concentration; logarithm expression) of a specimen drug, and anordinate axis indicates a ratio of relaxation in a rat-extractedspecimen. ◯ - - - ◯ indicates a specimen compound obtained in Example 9,and ● - - - ● indicates TKS159 hydrochloride. As a concentration of aspecimen drug grows higher, relaxation of a specimen is caused in aconcentration-dependent manner, and it is seen that action of a drugobtained in Example 9 is stronger as compared with TKS159 hydrochloride.

BEST MODE FOR CARRYING OUT THE INVENTION

4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideof the present invention or an acid addition salt thereof can beprepared by reacting 4-amino-5-chloro-2-methoxybenzoic acid having anoptionally protected amino group represented by the formula (I):

(wherein R¹ represents an optionally protected amino group) or areactive derivative thereof, with(2S,4S)-4-amino-2-hydroxymethylpyrrolidine having an optionallyprotected imino group represented by the formula (II):

(wherein R² represents a hydrogen atom or a protecting group for animino group) to prepare a compound represented by the formula (III):

(wherein R¹ and R² are each the same as defined above), and optionallyremoving a protecting group for an amino group or/and a protecting groupfor an imino group.

As described above, a compound represented by the formula (III) in whichat least one of an amino group or/and an imino group is protected with aprotecting group is important as an intermediate for synthesizing4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide(TM161) which is a novel compound, or an acid addition salt thereof.Also, when a protecting group for an amino group or/and a protectinggroup for an imino group is, like TM161, removed in a living body afteradministration of a compound (III) to a living body, a compound of theformula (III) can be used like TM161, since it exerts effect ofimproving the movement of the digestive tract more excellent than thatof TKS159 while avoiding side effect such as thrombus formation,arteritis and encephalomalacia. Examples of a protecting group for anamino group and a protecting group for an imino group include an acylgroup (e.g. acetyl group), a BOC group, and a benzyloxycarbonyl group. Aprotecting group which protects an amino group or/and an imino group andcan be eliminated in a living body has previously establishedsufficiently, and such protecting group which can be eliminated in aliving body may be adopted as a protecting group also in the presentinvention. Specifically, as a protecting group which can be eliminatedin a living body, an acyl group (e.g. lower alkylcarbonyl group such asacetyl and propionyl), and an alkyloxycarbonyl group (e.g. loweralkyloxycarbonyl group such as methyloxycarbonyl and ethyloxycarbonyl)are preferable.

4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideof the present invention or an acid addition salt thereof, which hashigh binding affinity for a serotonin receptor 4 (5HT₄) and does notcause arteritis, thrombus formation and the like is a metabolite of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, and can be prepared more preferably asfollows: that is, it can be prepared by subjecting4-amino-5-chloro-2-methoxybenzoic acid or a derivative in which an aminogroup thereof is protected, or a reactive derivative thereof (e.g. acidhalide, active ester, acid anhydride etc.) and(2S,4S)-4-amino-N-acyl-2-hydroxymethylpyrrolidine to a condensationreaction in a suitable medium optionally in the presence of a condensingagent. Examples of the acyl group include formyl, acetyl, propionyl andbenzoyl, and acetyl is preferable. A protecting group for an amino groupmay be the aforementioned acyl group.

The resulting compound is obtained as an acid addition salt in somecases depending on a condensation method, but when a basic compound isconverted into an acid addition salt, it may be converted into an acidaddition salt by dissolving it in a suitable solvent and adding adesired acid thereto. Herein, as a suitable medium used in acondensation reaction, a medium which is inert to the starting materialor a condensing agent such as tetrahydrofuran, dioxane, benzene,toluene, petroleum hydrocarbon (hexane, heptane, octane, petroleumbenzine etc.), dimethylformamide, pyridine, triethylamine, acetonitrile,and chloroform are preferably used. When4-amino-5-chloro-2-methoxybenzoic acid is converted into a reactivederivative, it includes an acid halide derivative such as acid chlorideor acid bromide derived from thionyl chloride or phosphorus tribromide,an acid anhydride such as mixed acid anhydride with ethylchlorocarbonate, and an active ester derived from ethyl alcohol orp-nitrophenol, and further, an acid imidazolide and an acid pyrrolideobtained by reaction with N, N-dicarbonyldiimidazole orN,N-carbonyldipyrrole. When these reactive derivatives are subjected toa reaction, it is better to use a base such as pyridine, picoline,N-ethylmorpholine, triethylamine and potassium carbonate. Certain caseswhere a condensing agent is optionally used refers to the case where4-amino-5-chloro-2-methoxybenzoic acid is subjected to a reactionwithout being converted into a reactive derivative and, in such cases, acondensing agent is used. Examples of the condensing agent used includeN,N-dicyclohexylcarbodiimide, 1,1-sulfinyldiimidazole,1,1-carbonyldiimidazole, titanium tetrachloride, phosphorus trichloride,phosphorus oxychloride, diethyl chlorophosphite, and o-phenylenechlorophosphite.

A condensation reaction can be preferably performed at room temperatureor under warming while stirring. The thus obtained4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-acyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideis produced as an acid addition salt in some cases and, when produced asa base form, it is converted into a suitable acid addition salt.Examples of the acid for converting into such acid addition salt includehydrogen chloride, hydrogen bromide, sulfuric acid, hydrogen iodide,carbonic acid, phosphoric acid, formic acid, acetic acid, propionicacid, glycolic acid, glucuronic acid, maleic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, benzoic acid, salicylic acid, phenylacetic acid,mandelic acid, lactic acid, succinic acid, tartaric acid, fumaric acid,and citric acid. For converting into an acid addition salt, a desiredacid addition salt can be obtained by mixing and stirring4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-acyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideproduced as a base with a desired acid among the aforementioned acids ina suitable solvent. An acid addition salt is usually a pharmaceuticallyacceptable salt.

4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-1-acyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereofobtained herein is converted into4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor acid addition salt thereof which can avoid side effect such asarteritis, thrombus formation, and encephalomalacia inevitably occurredin TKS159 or an acid addition salt thereof, via elimination of an acylgroup. Herein, elimination of such acyl group is accomplished byaddition of sodium hydroxide or potassium hydroxide in an alcohol(methyl alcohol, ethyl alcohol, propyl alcohol etc.), and heating themat reflux.

Thus, an ameliorant for improving the movement of the digestive tractwhich has high binding affinity for a serotonin receptor 4 (5HT₄) andcan avoid side effect occurred concomitantly in TKS159 or an acidaddition salt thereof such as arteritis and thrombus formation, that is,4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt which is a metabolite of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt can be obtained.

(2S,4S)-4-amino-2-hydroxymethylpyrrolidine having a protected amino acidused in the aforementioned process can be prepared by the followingmethod. (2S,4S)-4-amino-2-hydroxymethylpyrrolidine having a protectedimino group can be advantageously prepared in industrial scale byintroducing a protecting group into an imino group of4-hydroxy-L-proline alkyl ester to prepare anN-protected-4-hydroxy-L-proline alkyl ester, converting the hydroxylgroup of the thus prepared N-protected-4-hydroxy-L-proline alkyl esterinto a mesyloxy group to prepare an N-protected-4-mesyloxy-L-prolinealkyl ester, converting the mesyloxy group of the thus preparedN-protected-4-mesyloxy-L-proline alkyl ester into an azido group toprepare an N-protected-4-azido-L-proline alkyl ester, subjecting thethus prepared N-protected-4-azido-L-proline alkyl ester to a reducingreaction to prepare anN-protected-(2S,4S)-4-azido-2-hydroxymethylpyrrolidine, and furthersubjecting the thus preparedN-protected-(2S,4S)-4-azido-2-hydroxymethylpyrrolidine to a reducingreaction.

As a protecting group in this process, the aforementioned protectinggroup for an imino group is used, and an acetyl group is preferable. Asan alkyl group, a lower alkyl group having a carbon number of 1 to 4 ispreferable, and examples thereof include a methyl group and an ethylgroup. In addition, it is preferable that the first reduction reactionis performed using sodium borohydride as a reducing agent, and it ispreferable to perform the second reduction reaction by catalyticreduction.

4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof obtained herein, which is an ameliorantfor improving the movement of the digestive tract having high bindingaffinity for a serotonin receptor 4(5HT₄) and being capable of avoidingside effect that concomitantly occurs in association with TKS159 or anacid addition salt thereof, such as arteritis and thrombus formation, isformulated into a preparation together with a pharmaceuticallyacceptable suitable carrier, and is put into practice as a medicinalcomposition for improving the movement of the digestive tract.

Herein, examples of the pharmaceutically acceptable suitable carrierinclude excipients (e.g. lactose, glucose, potato starch, corn starch,carboxymethylcellulose, crystalline cellulose, and light silicicanhydride), disintegrators (e.g. starch, calciumcarboxymethylcellulose), lubricants (e.g. magnesium stearate, purifiedtalc, calcium stearate), binders (e.g. starch paste solution,hydroxypropylcellulose solution, carboxymethylcellulose solution, gumarabic solution, gelatin solution, hydroxypropylmethylcellulosesolution), coloring agents and corrigents. These are selected inconformity with a desired dosage form, prescribed, and formulated into apreparation.

As the preparation of a formulated medicinal composition of the presentinvention for improving the movement of the digestive tract comprising4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof which is an ameliorant for improvingthe movement of the digestive tract, having high binding affinity for aserotonin receptor 4 (5HT₄) and being capable of avoiding side effectthat concomitantly occurs in association with TKS159 or an acid additionsalt thereof such as arteritis and thrombus formation and a suitablecarrier, there are exemplified tablets, capsules, fine granules,granules, injectables, syrups, and dry syrups. A carrier suitable ineach of those preparations is used by selecting from the aforementionedcarriers. For example, when a preparation which is a formulatedmedicinal composition for improving the movement of the digestive tractis a tablet, a prescribed amount of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, which is an ameliorant for improvingthe movement of the digestive tract, having high binding affinity for aserotonin receptor 4 (5HT₄) and being capable of avoiding side effectthat concomitantly occurs in association with TKS159 or an acid additionsalt thereof such as arteritis and thrombus formation, is placed into afluidized bed granulator together with a prescribed amount of lactoseand crystalline cellulose, and then granulation is performed while anaqueous binder solution is sprayed. Then, a disintegrating agent and alubricant are added, followed by mixing. A granulated material obtainedherein is compressed to a tablet having a prescribed size and weightwith a tableting machine.

A content of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof which is an ameliorant for improving ofthe movement of the tract having high binding affinity for a serotoninreceptor 4 (5HT₄) and being capable of avoiding side effect thatconcomitantly occurs in association with TKS159 or an acid addition saltthereof such as arteritis and thrombus formation, as an activeingredient contained in a preparation, is associated with a total doseof an active ingredient per day, and is 0.05 to 10 mg/single dose.Administration frequency is increased or decreased by determination of aphysician depending on symptom, administration period, and sensitivityof an individual to an active ingredient, and administration once tothree times per day is general.

4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrollidinyl]benzamideor an acid addition salt thereof which is an ameliorant for improvingthe movement of the digestive tract having high binding affinity for aserotonin receptor 4 (5HT₄) and being capable of avoiding side effectthat concomitantly occurs in association with TKS159 or an acid additionsalt thereof, such as arteritis and thrombus formation, as an activeingredient in the present invention, has weaker acute toxicity than thatof TKS159 or an acid addition salt thereof in oral administration in anacute toxicity test, and is therefore suitable in oral administration.There are provided an ameliorant for improving the movement of thedigestive tract comprising, as an active ingredient,4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pirrolidinyl]benzamideor an acid addition salt thereof which is a metabolite of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, having high biding affinity for aserotonin receptor 4 (5HT₄) and causing no arteritis and thrombusformation, and a medicinal composition for improving the movement of thedigestive tract comprising the same and a carrier.

EXAMPLES Example 1 Measurement of Action of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamidemonohydrochloride on serotonin receptor 4

Corpus striatum extracted from a Hartley male guinea pig was homogenizedin a 50 mM HEPES-NaOH buffer (pH 7.4), and centrifugation and suspensionwere repeated to prepare a serotonin receptor 4 sample. The receptorsample was reacted with a solution containing a 0.1 nM radioactiveligand of [³H]-GR113808 and the specimen drug obtained in Example 3 at aprescribed concentration. Then, the solution was filtered by suctionusing a multifilter MF-12G (glass filter (provided with Whatman GF/C)),and radioactivity of the filter was measured using a scintillationcounter (LS6500 Beckman), so that affinity of the specimen drug for aserotonin receptor 4 was measured. Separately, the same procedure wasalso performed regarding TKS159 hydrochloride, and the affinity wascompared.

The results are shown in FIG. 1. IC₅₀ is 0.25 μM, which is a lowerconcentration than 0.45 μM of TKS159 hydrochloride.

Example 2 Measurement of action of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamidemonohydrochloride on dopamine D₂ receptor

Corpus striatum extracted from a Wister male rat was homogenized in a 50mM Tris-HCl buffer (pH 7.7), and centrifugation and suspension wererepeated to prepare a dopamine D₂ receptor sample. The receptor samplewas reacted with a solution containing a 0.25 nM radioactive ligand of[³H]-spiperone and the specimen drug obtained in Example 3 at aprescribed concentration. Then, the solution was filtered by suctionusing a multifilter MF-12G (glass filter (provided with Whatman GF/C)),and radioactivity of the filter was measured using a scintillationcounter (LS6500 Beckman), so that affinity of the specimen drug for adopamine D₂ receptor was measured. Separately, the same procedure wasalso performed regarding TKS159 hydrochloride, and the affinity wascompared.

The results are shown in FIG. 2. IC₅₀ is 34 μM, which is a higherconcentration than 3.8 μM of TKS159 hydrochloride.

Example 3 Synthesis of N-acetyl-4-hydroxy-L-proline ethyl ester

345 g of acetic anhydride was added dropwise to a suspension of 600 g of4-hydroxy-L-proline ethyl ester hydrochloride, 683 g of triethylamineand 2.4 L of chloroform at not higher than 10° C. while cooling. Afterstirring for 2 hours, water (0.6 L) was added, and the layers wereseparated. The organic layer was dried over magnesium sulfate, andconcentrated under reduced pressure to obtain 1020 g ofN-acetyl-4-hydroxy-L-proline ethyl ester as an oil.

IR (neat) ν cm⁻¹: 3402, 1740, 1626, 1456, 1278, 1195, 1085, 1035, 967,864, 568

Example 4 Synthesis of N-acetyl-4-mesyloxy-L-proline ethyl ester

457 g of methanesulfonyl chloride was added dropwise to a solution of1020 g of N-acetyl-4-hydroxy-L-proline ethyl ester, 435 g oftriethylamine and 1.9 L of chloroform at not higher than 15° C. whilecooling. After stirring for 30 minutes, 1N hydrochloric acid (0.6 L) wasadded, and the layers were separated. The organic layer was washed with5% aqueous sodium bicarbonate (600 g), washed with water (0.6 L), driedover magnesium sulfate, and concentrated under reduced pressure toobtain 802 g of N-acetyl-4-mesyloxy-L-proline ethyl ester as an oil.

IR (neat) ν cm⁻¹: 3462, 1742, 1652, 1422, 1353, 1268, 1196, 1175, 958,905, 531

Example 5 Synthesis of N-acetyl-4-azido-L-proline ethyl ester

243 g of sodium azide was added to a solution of 802 g ofN-acetyl-4-mesyloxy-L-proline ethyl ester and 2.4 L of DMF, and themixture was reacted at an inner temperature of 70° C. for 7 hours. Thereaction solution was cooled, poured into ice water (4.8 L), andextracted with chloroform (3.2 L). The organic layer was dried overmagnesium sulfate, and concentrated under reduced pressure to obtain 644g of N-acetyl-4-azido-L-proline ethyl ester as an oil.

IR (neat) ν cm⁻¹: 3472, 2109, 1746, 1656, 1418, 1370, 1269, 1195, 1055,1029, 615, 561

Example 6 Synthesis of(2S,4S)-N-acetyl-4-azido-2-hydroxymethyl-pyrrolidine

644 g of N-acetyl-4-azido-L-proline ethyl ester dissolved in 700 ml ofethanol was added dropwise to a suspension of 2.5 L of ethanol and 162 gof sodium borohydride at not higher than 10° C. while cooling. Afterovernight reaction, 35% hydrochloric acid (594 g) was added dropwise tothe above mixture at not higher than 20° C. while cooling, and thesolution was neutralized with sodium bicarbonate (24 g). Afterfiltration, the solution was concentrated under reduced pressure whilethe solvent was substituted with 1.3 L of isopropyl alcohol, thereby toobtain 534 g of (2S,4S)-N-acetyl-4-azido-2-hydroxymethylpyrrolidine asan oil.

¹H—NMR (CDCL3) δ: 1.8 (1H, ddd), 2.1 (3H,s), 2.4 (1H,ddd), 2.9 (1H,d),3.5 (1H,dd), 3.8 (2H,m), 4.2 (1H,ddd), 4.3 (1H, m), 4.7 (1H,OH) IR(neat) ν cm⁻¹: 3371, 2104, 1626, 1445, 1362, 1327, 1269, 1048, 907, 617,560

Example 7 Synthesis of (2S,4S)-N-acetyl-4-amino-2-hydroxymethyl-pyrrolidine

92.4 g of 10% Pd—C was added to a solution of 534 g ofN-acetyl-4-azido-2-hydroxymethylpyrrolidine and 2.6 L of methanol, andthis was hydrogenated (30 hours) at a normal pressure until the rawmaterial disappeared, while the atmosphere in the container wassubstituted for hydrogen gas every one hour. After filtration, thesolution was concentrated under reduced pressure to obtain 411 g of (2S,4S)-N-acetyl-4-amino-2-hydroxymethylpyrrolidine, more specifically,(2S,4S)-(−)-1-acetyl-4-amino-2-hydroxymethyl-pyrrolidine as an oil.

[α]_(D) ²⁰=−57.1° (c=1.28, MeOH) IR (neat) ν cm⁻¹: 3343, 1625, 1446,1361, 1238, 1199, 1037, 957, 915, 757, 612

Example 8 Synthesis of4-acetylamino-5-chloro-2-methoxy-N-[(2S,4S)-1-acetyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide

9.84 g of 4-acetylamino-5-chloro-2-methoxybenzoic acid, and 4.5 g oftriethylamine were dissolved in 40 ml of dichloromethane, and 4.60 g ofethyl chlorocarbonate was added dropwise to the solution at not higherthan 10° C. After stirring at the same temperature for 30 minutes, asolution of 7.03 g of(2S,4S)-(−)-1-acetyl-4-amino-2-hydroxymethylpyrrolidine indichloromethane (20 ml) was added dropwise. After stirring at the sametemperature overnight, water (20 ml) was added, precipitated crystalswere filtered, and the resulting crystals were dried in a warm air at 50to 55° C. to obtain 11.74 g of4-acetylamino-5-chloro-2-methoxy-N-[(2S,4S)-1-acetyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide.

¹H—NMR (CDCL3) δ: 1.7 (1H, ddd), 2.1 (3H, s), 2.3 (3H, s), 2.5 (1H,ddd), 3.4 (1H, dd), 3.7 (1H, dd), 3.9 (1H, dd), 4.0 (3H, s), 4.1 (1H,dd), 4.3 (1H, m), 4.6 (2H, m), 7.8 (1H, s), 8.1 (1H, d), 8.2 (1H, s),8.4 (1H, s). ¹³C—NMR (DMSO-d6), δ: 28.13, 28.97, 38.38, 52.04, 53.24,59.66, 61.39, 63.20, 67.02, 124.58, 135.98, 143.55, 161.13, 161.18,167.88, 141.17, 174.37. IR (KBr) ν cm⁻¹: 3251, 1697, 1629, 1563, 1511,1457, 1397, 1309, 1238, 1194, 1080, 1049, 1013, 980, 638

Example 9 Synthesis of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamidemonohydrochloride

11.74 g of4-acetylamino-5-chloro-2-methoxy-N-[(2S,4S)-1-acetyl-2-hydroxymethyl-4-pyrrolidinyl]benzamidewas dissolved in ethyl alcohol (60 ml), and sodium hydroxide (2.7 g) wasadded thereto. The mixture was heated at reflux for 8.5 hours. Afteraddition of water (20 ml), the mixture was stirred at room temperaturefor 1 hour to filter insolubles off, and washed sufficiently with water(50 ml). The filtrate was concentrated under reduced pressure, n-butylalcohol (50 ml) and a saturated brine solution (20 ml) were added to theresulting residue, and the layers were separated, followed byre-extraction with n-butyl alcohol (30 ml). The extract was concentratedunder reduced pressure, methyl alcohol (50 ml) was added to the residueto dissolve it, and 18% (w/w) hydrochloric acid-containing methylalcohol (6.5 g) was gradually added to adjust to a pH 6. Afterice-cooling, precipitated crystals were filtered, and washed with asmall amount of methyl alcohol. The resulting crystals wererecrystallized from ethyl alcohol to obtain 5.5 g of the objective4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamidemonohydrochloride. mp 219-222° C., [α]_(D) ²⁰: +4.20 (c=1.00, EtOH)

¹H—NMR(CD₃OD) δ: 1.98 (1H, ddd, J=13.6, 8.1, 5.5 Hz), 2.58 (1H, ddd,H=13.6, 8.3, 8.3 Hz), 3.38 (1H, dd, J=12.0, 4.0 Hz), 3.54 (1H, dd,J=12.0, 7.0 Hz), 3.79 (1H, dd, J=11.5, 5.1 Hz), 3.80 (1H, m), 3.92 (3H,s), 3.92 (1H, dd, J=11.5, 3.0 Hz), 4.68 (1H, m), 6.51 (1H, s), 7.82 (1H,s) ¹³C—NMR (CD₃OD) δ: 33.17, 50.31, 52.18, 56.67, 61.03, 62.33, 98.54,110.86, 111.62, 133.29, 150.75, 159.83, 167.22. IR (KBr) ν cm⁻¹: 3418,3385, 3325, 3212, 2437, 1637, 1588, 1455, 1207, 1161, 1048, 832.

Example 10

Using three beagle dogs as a test animal,4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamidemonohydrochloride obtained in Example 9 was repeatedly administeredorally at a dose of 100 mg/kg once a day for 4 weeks. Thereafter, theanimals were sacrificed by exsanguination from carotid artery underanesthesia, and the brain, aorta, heart, lung, and liver were extracted.These organs were examined with naked eyes, fixed with a 0.1%phosphate-buffered 10% formalin solution, and stored. Each organ wasembedded in paraffin, and sliced to prepare a hematoxine orange-stainedsample. Pathohistological test on the sections was performed using alight microscope. Abnormality was not seen in any organ with naked eyes.In addition, abnormality was not seen also in a pathohistological test,and encephalomalacia, arteritis and thrombus formation were notrecognized.

Example 11

Five Sprague-Dawley male rats, 4 week age, weighing each 160.3 to 169.5g, were reared for 8 days for quarantine and training were handled asone group, and they were grouped into four groups of a control group, a300 mg/kg administration, a 1000 mg/kg administration, and a 2000 mg/kgadministration.4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide monohydrochloride obtained in Example 9 was ground with amortar, the powder was added so that the compound was contained at 300mg, 1000 mg or 2000 mg in 10 ml of a 0.5% aqueous methylcellulosesolution (manufactured by Wako Pure Chemical Industries, Ltd.; preparedusing Japanese Pharmacopoeia injectable water), and the solution wasstirred to prepare an administration specimen. Administration specimensfor 7 days were prepared at one time, once per week, stored in arefrigerator, and used. One-time dose was defined to be 10 ml/kg, andthe specimen was forcibly administered orally at 9 o'clock to 12 o'clockfor 28 days once a day using a rat stomach tube. Only a 0.5% aqueousmethylcellulose solution was administered at 10 ml/kg to a controlgroup.

During training and drug administration period, a solid feed (CE-2manufactured by CLEA Japan Inc.) and tap water were freely given.

After termination of the administration period, all cases were subjectedto necropsy, an organ and a tissue such as brain, heart, aorta, lung,pancreas, liver, and cava were observed with naked eyes andhistologically, and subjected to a pathohistological test. Abnormalitywas not seen with naked eyes in any organ. In addition, also in apathohistological test, abnormality was not seen, and encephalomalacia,arteritis and thrombus formation were not recognized.

Example 12 Measurement of relaxation reaction of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamidemonohydrochloride in rat-extracted sample

Regarding the drug obtained in Example 9, a degree of action ofpromoting the movement of the digestive tract was measured using anesophagus sample extracted from a rat.

An esophagus in a chest cavity was extracted from a Wister male rat, andmuscularis propria sample containing longitudinal muscle and circularmuscle was removed to prepare a muscularis mucosae sample having alength of about 2 cm. The sample was immersed in a nutrient solution(containing NaCl 118.5, KCl4.7, CaCl₂ 1.3, MgSO₄ 0.6, NaHCO₃ 25.0,KH₂PO₄ 1.2, and glucose 11.1 (unit mM)), and constriction of the sampleand stability of the constriction were confirmed at 32° C. using 3×10⁻⁶M carbachol while a 95% O₂/5% CO₂ mixed gas was flown, each 1 μM ofmethysergide, ketanserin and granisetron were added, the drug obtainedin Example 9 was accumulatively applied at a common ratio of 3 after 30minutes, and a degree of relaxation was isotonically (stationarytension; about 0.5 g) measured via a transducer. Separately, the sameprocedure was also performed regarding TKS159 hydrochloride, and anintensity of the action was compared.

The results are shown in FIG. 3. EC₅₀ was 0.7 μM, which is a lowerconcentration than 1.1 μM of TKS159 hydrochloride.

Example 13

Using a ddy male mouse, the drug obtained in Example 9 and TKS159 weresuspended in 0.5% methylcellulose for oral administration, and weredissolved in a physiological saline for intravenous administration. Thiswas administered by a forced oral administration method and anintravenous administration method using a probe, and acute toxicity wasobserved. Dose mg/kg Administration Administration Dose method materialmg/kg Survival Oral Example 9 drug 1080 5 survivals among 5administration 1320 3 survivals among 5 TKS159 720 3 survivals among 4hydrochloride 880 1 survival among 5 1080 No survival among 2Intravenous Example 9 drug 32 6 survivals among 6 administration 48 1survival among 5 59 1 survival among 6 72 1 survival among 6 TKS159 72 5survivals among 6 hydrochloride 88 4 survivals among 6 108 4 survivalsamong 6 132 No survival among 6

Example 14

50 g of the drug obtained in Example 9, 650 g of lactose, and 200 g ofcrystalline cellulose were weighed, this was placed into a fluidizedlayer granulator, and sprayed with a 5% aqueous solution of 30 g of abinder hydroxypropylcellulose to obtain granulated powders. Then, 50 gof a disintegrating agent calcium carboxymethylcellulose and 20 g of alubricant magnesium stearate were added to granulated powders, and thesewere mixed. The resulting granulated powders for compression were moldedunder pressure to obtain tablets, one tablet weighing 100 mg.

Separately, using tablets obtained herein, a film coating solutionprepared using 48 g of hydroxypropylmethylcellulose, 7.2 g ofpolyethylene glycol 6000, 1.8 g of talc, 3 g of titanium oxide and 550cc of purified water was coated to a weight of one tablet of 105 mg, toobtain a film-coated tablet.

Reference Example

TKS159 was repeatedly administered orally to each group of two malebeagle dogs for 4 weeks at a dose of 10, 30 and 100 mg/kg, these wereobserved and, as a result, thrombus formation was recognized in a lungartery and a heart coronary artery, and slight bleeding was recognizedin a cavity surrounding a blood vessel in a cerebral parenchyma in adeath case of a 100 mg/kg administration group. In a survival case of a100 mg/kg administration group, big thrombus formation was recognized ina left ventricle, and thrombus formation was recognized in a kidneyarcuate artery and an interlobar artery. Separately, beagle dogs (femaleand male) were divided into 4 groups consisting of 6, 4, 4 and 6 dogsand, among them, to 3 groups were repeatedly administered orally TKS 159at a dose of 2.5, 6.0 and 15.0 mg/kg, and to a control group wasrepeatedly administered orally an excipient, for 13 weeks, andobservation of the general status and various tests were performed.Further, regarding a control group and a case of a part of a 15.0 mg/kgadministration group, after a repeated administration period for 13weeks, a recovery test of no administration of a drug was performed for4 weeks, and then the same test was performed. As a result of the test,in two cases of the 15.0 mg/kg administration group, arteritis wasrecognized, and a site thereof was around a spinal nerve root, and costaartery, cerebral pia mater, thymus and bladder. In other one case,necrosis of an artery septum and surrounding cell infiltration wererecognized in cerebellumpiamater, lung, coronary artery, liver, bladder,stomach, vagina, intestine and diaphragm. Separately, beagle dogs(female and male) were divided into 4 groups containing 5, 3, 3 and 5dogs and, among them, to 3 groups was repeatedly administered orallyTKS159 at a dose of 0.25, 0.75 and 2.25 mg/kg, to a control group wasrepeatedly administered an excipient orally, for 52 weeks, andobservation of the general status and various tests were performed.Further, regarding a control group and a case of a part of a 2.25 mg/kgadministration group, after a repeated administration period for 52weeks, a recovery test of no administration of a drug was performed for4 weeks, and then the same test was performed. As a result of a test, ina 52 week repeated administration toxicity test, arteritis was observedin thighbone marrow and mediastinal lymph node in one case among male 5cases of the 2.25 mg/kg administration group, and malacia was seen inpiriform lobe and hippocampus in other one case.

INDUSTRIAL APPLICABILITY

In the present invention, an ameliorant for improving the movement ofthe digestive tract comprising, as an active ingredient,4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof which has high binding affinity for aserotonin receptor 4 (5HT₄) and capable of avoiding side effectoccurrence such as thrombus formation and arteritis concomitantly causedinevitably in administration of4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamideor an acid addition salt thereof, or a medicinal composition containingthe ameliorant as an active ingredient and a pharmaceutically acceptablecarrier can be provided. Since it is an indispensable attribute for amedicinal compound that side effect is avoided as much as possible, theameliorant of the present invention is effective and safe with no sideeffect occurrence, and thus it is useful as a medicine.

1. An ameliorant for improving the movement of the digestive tract, comprising as an active ingredient 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof which has high binding affinity for a serotonin receptor 4 (5HT₄) and does not cause arteritis and thrombus formation.
 2. A medicinal composition for improving the movement of the digestive tract, comprising as an active ingredient 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof which has high binding affinity for a serotonin receptor 4 (5HT₄) and does not cause arteritis and thrombus formation, and a pharmaceutically acceptable carrier.
 3. A treating method for promoting the movement of the digestive tract, which comprises using an ameliorant for improving the movement of the digestive tract comprising as an active ingredient 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof which has high binding affinity for a serotonin receptor 4 (5HT₄) and does not cause arteritis and thrombus formation, or using a medicinal composition for improving the movement of the digestive tract comprising the ameliorant and a pharmaceutically acceptable carrier.
 4. A method for improving the movement of the digestive tract of a human or an animal while avoiding occurrence of arteritis, thrombus formation or encephalomalacia, which comprises administering 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof or a medicinal composition containing the ameliorant and a pharmaceutically acceptable carrier to a human or a mammal.
 5. 4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof.
 6. 4-Amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide in which an amino group at position 4 or/and an amino group of the pyrrolidinyl group is optionally protected, or an acid addition salt thereof.
 7. A process for preparing 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof, which comprises reacting 4-amino-5-chloro-2-methoxybenzoic acid having an optionally protected amino group, or a reactive derivative thereof with (2S,4S)-4-amino-N-acyl-2-hydroxymethylpyrrolidine to obtain 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-acyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide or an acid addition salt thereof, and eliminating a protecting group and the acyl group, when a protecting group is used in the acyl group.
 8. (2S,4S)-4-amino-N-acyl-2-hydroxymethylpyrrolidine having an optionally protected amino group.
 9. The compound according to claim 8, wherein a protecting group for an amino group is an acyl group, and the said acyl group and an acyl group of N-acyl are selected from formyl, acetyl, propionyl and benzoyl.
 10. The compound according to claim 8, wherein the acyl group is acetyl. 